Process for the produciton of cross-linked gelatin beadlets

ABSTRACT

The invention provides a process for the production of cross-linked beadlets containing one or more active ingredients selected from the group of a fat-soluble vitamin active material, a carotenoid and a polyunsaturated fatty acid, the process comprising treating a dry particulate form at a temperature in the range of from 90° C. to 140° C. for a time period of from 30 seconds to 30 minutes or from 1 minute to 10 minutes or from 3 minutes to 7 minutes.

FIELD OF THE INVENTION

The present invention relates to a process for the production ofbeadlets with a high concentration of an active ingredient selected froma fat soluble vitamin, a carotenoid and a polyunsaturated fatty acid, tothe resulting beadlets and to compositions containing them.

SUMMARY OF THE INVENTION

More particularly the invention provides a process for the production ofcross-linked beadlets containing one or more active ingredients selectedfrom the group of a fat-soluble vitamin active material, a carotenoidand a polyunsaturated fatty acid, the process comprising treating a dryparticulate form at a temperature in the range of from 90° C. to 140° C.for a time period of from 30 seconds to 30 minutes or from 1 minute to10 minutes or from 3 minutes to 7 minutes.

DETAILED DESCRIPTION

Examples of a fat-soluble vitamin active material include vitaminbearing oils, provitamins and pure or substantially pure vitamins, bothnatural and synthetic, or chemical derivatives thereof and mixturesthereof. Of particular interest is a vitamin selected from the group ofvitamins A, D, E and K, and derivatives thereof. For example, the term“Vitamin E” includes synthetically manufactured tocopherols or a mixtureof natural tocopherols. Examples of vitamin derivatives include vitaminA acetate, vitamin A palmitate and vitamin E acetate. An example for avitamin D-active material is vitamin D₃. As a particular example, theprocess of the present invention may result in a beadlet containing avitamin A-active material and a vitamin D-active material, e.g. vitaminA and vitamin D₃.

In one embodiment the process of the invention may involve Vitamin A asfat-soluble vitamin active material in a total concentration in therange of from 500,000 IU vitamin A/g beadlet to 1,500,000 IU vitamin A/gbeadlet, in the range of from 750,000 IU vitamin A/g beadlet to1,500,000 IU vitamin A/g beadlet, or in the range of from 750,000 IUvitamin A/g beadlet to 1,300,000 IU vitamin A/g beadlet, e.g. vitamin Amay be present in the beadlet in a total concentration of 500,000±35,000IU active ingredient/g beadlet, 750,000±35,000 IU active ingredient/gbeadlet, of 1,000,000±35,000 IU active ingredient/g beadlet, or of1,100,000±35,000 IU active ingredient/g beadlet. Vitamin D asfat-soluble vitamin active material maybe present in the range of from100,000 IU vitamin D/g beadlet to 500,000 IU vitamin D/g beadlet or inthe range of from 100,000 IU vitamin D/g beadlet to 200,000 IU vitaminD/g beadlet, vitamin E as fat-soluble vitamin active material may bepresent in the range of from 50% to 75% vitamin E.

Examples for a carotenoid include β-carotene, lycopene, zeaxanthin,astaxanthin, lutein, capsanthin and cryptoxanthin.

In one embodiment the process of the invention may involve a carotenoidin a total concentration in the range of from 5% to 20%, in the range offrom 5% to 15%, or in the range of from 7% to 15%.

Examples for a polyunsaturated fatty acid, as triglyceride and/orethylester, include arachidonic acid, eicosapentaenoic acid,docosahexaenoic acid and γ-linolenic acid and/or ethylester.

In one embodiment the process of the invention may involve apolyunsaturated fatty acid as triglyceride in a total concentration inthe range of from 20% to 50%, in the range of from 25% to 40%, or in therange of from 28% to 38%.

The dry particulate forms used in the process of the present inventionmay be prepared by any procedure known to the skilled artisan, e.g. byforming an aqueous emulsion containing the active ingredient, anemulsifier, a texturing agent and a reducing sugar, followed byconverting the emulsion to a dry particulate form containing thenon-aqueous constituents of said emulsion.

Examples for an emulsifier are gelatine and ascorbyl palmitate. Gelatineis an emulsifier which at the same time functions as a texturing agent.Any gelatine which has a “bloom” in the range of practically zero toabout 300 can be employed in the practice of the present invention. BothType A and Type B gelatine can be employed. The preferred gelatine usedis Bloom 140, but gelatine Bloom 30 or Bloom 75 would be possible aswell. In the presence of gelatine no additional texturing agent maybenecessary.

The concentration of the emulsifier depends on the kind of emulsifierused, e.g. gelatine maybe present in a concentration in the range offrom 25% to 35%, or less.

Examples for a texturing agent beyond gelatine include carrageenan,modified starch, modified cellulose, xanthan gum, acacia gum, pectins,guar, caroub gums, maltodextrines and alginates.

The concentration of the texturing agent depends on the kind oftexturing agent used and maybe, e.g., in the range of from 0% to 15%.

Examples for a reducing sugar are fructose, glucose, lactose, maltose,xylose, arabinose, ribose and sucrose. One type of sugar maybe used or amixture of two or more sugars. The reducing sugar may be added as suchor in the form of a syrup, e.g. fructose or glucose syrop.

The concentration of the reducing sugar depends on the kind of reducingsugar used and maybe, e.g., in the range of from 2% to 10%, or in aratio of gelatine:sugar in the range of from 3:1 to 7:1, e.g. 5:1.

Small quantities of other ingredients may be incorporated includingantioxidants like 6-ethoxy-1,2-dihydroxy-2,2,4-trimethylquinoline(ethoxyquine), 3,5-di-tertiary-4-butyl hydroxytoluene (BHT)and3-tertiarybutyl-hydroxyanisole (BHA), humectants, such as glycerol,sorbitol, polyethylene glycol, propylene glycol, extenders andsolubilizers.

As a typical example gelatine and a suitable sugar may be dissolved inwater previously mixed with glycerin. The dissolution may last at 65-70°C. for, e.g., about 30 minutes. Then, e.g., the vitamin A with theantioxidant may be added and emulsified. The pre-emulsification may bedone with a colloid mill, e.g., based on a rotor/stator principle. Thepre-emulsification may be hold for between 15 and 30 minutes at arotation speed of the rotor between 500 and 1500 rpm and may then passthrough a high pressure homogeniser resulting in a conversion of theemulsion to fine droplets.

In one example the conversion of emulsion droplets to “set up” particlesmay be attained by introducing a spray of emulsion droplets into anagitated cloud or suspension in air of the particles of the finelydispersed powder, e.g. by forcing the emulsion through a revolving sprayhead into a suspension in air of the powdered material, contained in andagitated by a revolving cylindrical drum, the drum and the spray headrotating in opposite directions so that the cloud or suspension of thepowder in air is swirling in a sense of rotation opposite to theentering emulsion spray.

Examples of the finely dispersed powder used in the process tocollect/coat the droplets of the emulsion include polysaccharides suchas starch and modified starch, and calcium silicate alone or a mixtureof calcium silicate with one of the following mixture components:microcrystalline cellulose, magnesium silicate, magnesium oxide, stearicacid, calcium stearate, magnesium stearate, hydrophilic silicic acid andkaolin. Coatings which consist of calcium silicate alone are preferred.The calcium silicate may be present wholly or partially in the form ofthe hydrate.

The calcium silicate particles are especially suitable when they have asize of less than 0.2 μm, especially less than 0.1 μm, and a specificsurface of at least about 80 m²/g to about 180 m²/g, preferably of about95 m²/g to 120 m²/g, and are agglomerated to aggregates having anaverage size of about 5-30 μm, preferably 5-20 μm. The SiO₂/CaO ratiolies between 1.65 and 2.65.

In coatings which consist of calcium silicate alone, the amount ofcalcium silicate may be in the range of from 2 wt. % to 12 wt. %,preferably in the range of from 4 wt. % to 9 wt. %.

In coatings consisting of a mixture of calcium silicate with one or moreof the aforementioned mixture components, the amount of the calciumsilicate mixture may be in the range of from 5 wt. % to 25 wt. %.

Optionally, the resulting dry particulate forms may be separated fromthe remaining finely dispersed powder. This may be accomplished byoperations which are conventional per se, including, e.g. simply to feedthe mixture of powder and dry particulate forms to a shaking screen of asize selected to retain the dry particulate forms while passing thecollecting powder.

For further processing those dry particulate forms containing the activematerial are preferred having a moisture content of less than 10% andpreferably between about 4 to 6 percent. If the moisture content ishigher the dry particulate forms maybe dried to the desired moisturecontent by various methods, e.g. by exposing them to air at roomtemperature or by moderate heating in a drying oven at 37° C. to 45° C.

The heat treatment may, e.g., be achieved in a batch or in a continuousprocess where the beadlet-residence time and temperature are controlled.

In the case of a fluid bed process, the beadlet is added either at thebeginning in the case of the batch process or constantly in the case ofa continuous fluid bed in a hot air or nitrogen stream having atemperature between 100 and 200° C.) preferably between 130-160° C. Thebeadlet temperature is raised in a few second to one minute above 100°C. enabling a quick and efficient reaction. The beadlet is ready after 5to 10 minutes. The beadlet is cooled at the end of the treatment.

In the case of a continuous flash treatment, the beadlet is fedcontinuously into a hot gas stream having a temperature between 100 and200° C., preferably between 130-160° C. The beadlet can be moved bymechanical stirring, e.g., above 300 rpm. The wall of the vessel used tomake this thermal treatment can also be heated to a temperature in therange of from 110 to 180° C. The desired crosslinking of the beadlet maybe reached in a time in the range of from 30 seconds to 10 minutes orfrom 1 minute to 10 minutes, with a maximum beadlet temperature in therange of from 90° C. to 140° C., preferably from 105° C. to 125° C.

The beadlet forms resulting from the inventive process have a core and asurface region, wherein the loss of active ingredients in the surfaceregion is reduced, and are also an object of the present invention.

Therefore, the present invention further provides a beadlet form havinga core and a surface region, wherein the core region contains, in a highconcentration, one or more active ingredients selected from the group ofa fat-soluble vitamin active material, a carotenoid and apolyunsaturated fatty acid, and the surface region contains less than10% of the total active ingredient content, preferably less than 5% ofthe total active ingredient content.

In one embodiment the present invention provides a beadlet formcontaining one or more active ingredients selected from the group ofVitamin A in a total concentration in the range of from 800,000 IUvitamin A/g beadlet to 1,500,000 IU vitamin A/g beadlet or in the rangeof from 950,000 IU vitamin A/g beadlet to 1,250,000 IU vitamin A/gbeadlet, in a total concentration in the range of from 100,000 IUvitamin D/g beadlet to 500,000 IU vitamin D/g beadlet or in the range offrom 100,000 IU vitamin D/g beadlet to 200,000 IU vitamin D/g beadlet,vitamin E in a total concentration in the range of from 50% to 75%, acarotenoid in a total concentration in the range of from 5 to 20% and apolyunsaturated fatty acid in a total concentration in the range of from5 to 50%, wherein the surface region contains less than 10%. of thetotal active ingredient content. In another embodiment the surfaceregion contains less than 5% of the total active ingredient content.

The beadlets are characterized by high stability and potency. Theyexhibit high stability when pelletized, e.g. they withstand thetemperature, moisture and pressure of a feed pelleting process withoutlosing their physical integrity. They are water insoluble and maintaintheir properties in relation to bioavailability.

Typical examples of beadlets of the present invention may, e.g. have thefollowing components: 30% to 45% of vitamin A, 0% to 2% of vitamin D₃,5% to 15% of 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (EMQ), 25% to35% of gelatine, 5% to 10% of fructose, 2% to 10% of glycerine, 5% to10% of calcium silicate, 0% to 25% of corn starch, 0% to 1% of ediblefat, and water.

EXAMPLE 1 Preparation of Beadlets containing 1,000,000 IU Vitamin A/gBeadlet Plus 200,000 IU Vitamin D₃/g Beadlet

Approximately 90 parts of gelatine Bloom 140 and 18 parts of fructosewere dissolved in 313.2 parts of water (containing 23.2 parts ofglycerin) by heating at 65° C. 158 parts of Vitamin A containing 24%ethoxyquin (assay 2.1 Mio. IU vitamin A per g) and 3.5 parts of vitaminD₃ (assay 20 Mio. IU vitamin D₃ per g) were then mixed with theresulting matrix, followed by pre-emulsification.

The beadlet was sprayed using as finely dispersed powder calciumsilicate. The average particle size of the beadlet was in the range offrom 200 μm to 300 μm.

The beadlet was divided into two groups: one group was treated using aclassical heated slow mixer without sufficient control of the thermalhistory of the beadlet, and the other group was treated by a fluidizedbed, i.e. a batch process with an apparatus where the temperature andresidence time of the beadlet can be controlled. The results arecompared in the following table: heated slow fluidized mixer bed VitaminA content after 1,025,000 1,050,000 crosslinking (IU/g) Vitamin A Loss(%) 3-4 0-1 Surface vitamin A (%)  8-10 1-2 Crosslinking grade (%) 76%82%

In the fluidized bed the temperature was controlled between 100 and 115°C. for 5 minutes. In the heated slow mixer, the beadlet was heated forabout 15 minutes at a temperature raising from 90° C. to 124° C.

EXAMPLE 2 Preparation of Beadlets containing 1,000,000 IU Vitamin A/gBeadlet

Approximately 100 parts of gelatine Bloom 140 and 20 parts of fructosewere dissolved in 308.2 parts of water (containing 13.2 parts ofglycerin) by heating at 65° C. 170 parts of Vitamin A containing 24%ethoxyquin (assay 2.1 Mio. IU vitamin A per g) were then mixed with theresulting matrix, followed by pre-emulsification.

The beadlet was sprayed using as finely dispersed powder calciumsilicate. The average particle size of the beadlet was in the range offrom 180 μm to 270 μm.

The beadlet was divided into three groups: the first group was treatedusing a classical heated slow mixer as in Example 1, the second groupwas treated by a fluidized bed as in Example 1, the third group wastreated by a continuous flash treatment in diluted phase wherein theflash treatment is ensured by a combination of pneumatic transport andmechanical transport. The results are compared in the following table:heated slow fluidized flash mixer bed treatment Vitamin A content after1,119,000 1,146,000 1,143,000 crosslinking (IU/g) Vitamin A Loss (%) 3-40-1 0-1 Surface vitamin A (%)  8-10   2-2.5 3-5 Crosslinking grade (%)50-80 50-80 50-80

In the fluidized bed the temperature was controlled between 110 and 120°C. for 5 minutes. In the flash treatment, the beadlet was treated for 1to 4 minutes at a temperature raising from 115° C. to 125° C. In theheated slow mixer, the beadlet was heated for about 20 minutes at atemperature raising from 70° C. to 124° C.

EXAMPLE 3 Stability of Beadlets containing a High Concentration ofVitamin A

Typical stability performance in terms of retention time after a storagetime of 4 weeks at 40° C. and 75% rH for the cross-linked beadlets ofExample 1 and Example 2 are about 90-95% which is comparable to standardcross-linked vitamin A forms containing 500′00 IU vitamin A/g activeingredient.

EXAMPLE 4 Preparation of Beadlets containing 1,000,000 IU Vitamin A/gBeadlet

Approximately 100 parts of gelatine Bloom 140 and 20 parts of fructosewere dissolved in 308.2 parts of water (containing 13.2 parts ofglycerin) by heating at 65° C. 170 parts of Vitamin A containing 24%ethoxyquin (assay 2.1 Mio. IU vitamin A per g) were then mixed with theresulting matrix, followed by pre-emulsification.

The beadlet was sprayed using as finely dispersed powder calciumsilicate. The average particle size of the beadlet was in the range offrom 200 μm to 300 μm.

The beadlets of 3 lots were treated by a continuous flash treatment indiluted phase wherein the flash treatment is ensured by a combination ofpneumatic transport and mechanical transport. The results are comparedin the following table: Lot 1 Lot 2 Lot 3 Vitamin A content after1,064,808 1,051,641 1,077,224 crosslinking (IU/g) Vitamin A Loss (%) <1<1 <1 Surface vitamin A (%) 3.7 4.0 3.5 Crosslinking grade (%) 60-8560-85 60-85

In the flash treatment, the beadlet was treated for 1 to 5 minutes at atemperature raising from 105° C. to 115° C.

EXAMPLE 5 Stability of Beadlets containing a High Concentration ofVitamin A

Typical stability performances in terms of retention time after astorage time of 4 weeks at 40° C. and 75% rH for the cross-linkedbeadlets of Example 4 are about 95-100% which are comparable to standardcross-linked vitamin A forms containing 500′00 IU vitamin A/g activeingredient.

EXAMPLE 6 Preparation of Beadlets containing 1,000,000 IU Vitamin A/gBeadlet Plus 200,000 IU Vitamin D₃/g Beadlet

Approximately 90 parts of gelatine Bloom 140 and 18 parts of fructosewere dissolved in 313.2 parts of water (containing 23.2 parts ofglycerin) by heating at 65° C. 158 parts of Vitamin A containing 24%ethoxyquin (assay 2.1 Mio. IU vitamin A per g) and 3.5 parts of vitaminD₃ (assay 20 Mio. IU vitamin D₃ per g) were then mixed with theresulting matrix, followed by pre-emulsification.

The beadlet was sprayed using as finely dispersed powder calciumsilicate. The average particle size of the beadlet was in the range offrom 200 μm to 300 μm.

The beadlets of 3 lots were treated treated by a continuous flashtreatment in diluted phase wherein the flash treatment is ensured by acombination of pneumatic transport and mechanical transport. The resultsare compared in the following table: Lot 1 Lot 2 Lot 3 Vitamin A contentafter 1,105,039 1,074,633 1,077,470 crosslinking (IU/g) Vitamin D3content after 218,617 214,813 217,858 crosslinking (IU/g) Vitamin A Loss(%) <1 <1 <1 Surface vitamin A (%) 4.7 4.7 4.6 Crosslinking grade (%)60-85 60-85 60-85

In the flash treatment, the beadlet was treated for 1 to 5 minutes at atemperature raising from 105° C. to 115° C.

EXAMPLE 7 Stability of Beadlets containing a High Concentration ofVitamin A and D3

Typical stability performances in terms of retention time after astorage time of 4 weeks at 40° C. and 75% rH for the cross-linkedbeadlets of Example 6 are about 95-100% and about 100% for vitamin A andD3 respectively, which are comparable to standard cross-linked vitaminAD3 forms containing 500′00 IU vitamin A/g and 100′000 IU vitamin D3/gactive ingredient.

1-11. (canceled)
 12. A process for the production of cross-linkedbeadlets containing one or more active ingredients selected from thegroup of a fat-soluble vitamin active material, a carotenoid and apolyunsaturated fatty acid, which comprises the steps of forming anemulsion containing the active ingredients, an emulsifier and a reducingsugar, converting the emulsion to droplets, coating the droplets withfinely dispersed powder, separating a dry particulate form from theremaining finely dispersed powder, and heat treating said particulateform, characterized in that the dry particulate form is heat treated ata temperature in the range of from 90° C. to 140° C. for a time periodof from 30 seconds to 30 minutes or from 1 minute to 10 minutes or from3 minutes to 7 minutes in such a way that the final beadlet forms have acore and a surface region, wherein the core region contains, in a highconcentration, the active˜ingredients and the surface region containsless than 10% of the total active ingredient content.
 13. The processaccording to claim 12 wherein the fat-soluble vitamin active material isselected from vitamin A, vitamin D and vitamin E, the carotenoid isselected from β-carotene, lycopene, zeaxanthin, astaxanthin, lutein,capsanthin and cryptoxanthin and the polyunsaturated fatty acid isselected from arachidonic acid, eicosapentaenoic acid, docosahexaenoicacid and γ-linolenic acid and triglycerides and ethylesters thereof. 14.The process according to claim 13 wherein the concentration of thefat-soluble vitamin active material, the carotenoid and thepolyunsaturated fatty acid is selected from a total concentration in therange of from 500,000 IU vitamin Mg beadlet to 1,500,000 IU vitamin A/gbeadlet, in the range of from 100,000 IU vitamin D/g beadlet to 500,000IU vitamin D/g beadlet, in the range of from 50% to 75% vitamin E, inthe range of from 5% to 20% of carotenoid and in the range of from 20%to 50% polyunsaturated fatty acid as triglyceride.
 15. The processaccording to claim 12 wherein as finely dispersed powder calciumsilicate is used.
 16. The process according to claim 12 wherein the dryparticulate forms have a moisture content of less than 10%.
 17. Theprocess according to claim 12 wherein the heat treatment is achieved ina batch or in a continuous process where the beadlet residence time andtemperature are controlled.
 18. The process according to claim 12wherein the beadlet is added in a hot air or nitrogen stream having atemperature between 100 and 200° C.
 19. The process according to claim12 wherein after addition of the dry particulate form the temperature israised in a time in the range of from a few seconds to 1 minute above100° C.
 20. The process according to claim 12 wherein heating takesplace at a maximum beadlet temperature in the range of from 110° C. to140° C.
 21. A cross-linked beadlet form having a core and a surfaceregion, wherein the core region contains, in a high concentration, oneor more active ingredients selected from the group of a fat-solublevitamin active material, a carotenoid and a polyunsaturated fatty acid,and the surface region contains less than 10% or less than 5% of thetotal active ingredient content.
 22. A cross-linked beadlet formcontaining one or more active ingredients selected from the group ofVitamin A in a total concentration in the range of from 800,000 IUvitamin A/g beadlet to 1,500,000 IU vitamin Mg beadlet, in a totalconcentration in the range of from 100,000 IU vitamin D/g beadlet to500,000 IU vitamin D/g beadlet, vitamin E in a total concentration inthe range of from 50% to 75%, a carotenoid in a total concentration inthe range of from 5 to 20% and a polyunsaturated fatty acid in a totalconcentration in the range from 5 to 50%, wherein the surface regioncontains less than 10% or less than 5% of the total active ingredientcontent.
 23. The cross-linked beadlet form according to claim 22 havingthe following components: 30% to 45% of vitamin A, 0% to 2% of vitaminD₃, 5% to 15% of 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, asemulsifier 25% to 35% of gelatine, as reducing sugar 5% to 10% offructose, 2% to 10% of glycerine, 5% to 10% of calcium silicate, 0% to25% of corn starch, 0% to 1% of edible fat, and water.